JP2006514934A - Use of loxapine or amoxapine for the manufacture of drugs for the treatment of pain - Google Patents

Abstract

Loxapine, amoxapine, or salts or prodrugs of either, is effective in alleviating pain, particularly headache pain such as migraine, cluster headaches and tension headaches. Preferably the loxapine or amoxapine is administered systemically, most preferably by inhalation.

Description

Background of the Invention

  [0001] The present invention relates to treatment and control of pain by administering to a subject in need of treatment or control of pain an effective amount of loxapine or amoxapine or a substance that supplies loxapine or amoxapine in the body. More specifically, the present invention relates to the treatment and control of pain by systemically administering loxapine, amoxapine, or a substance that supplies loxapine or amoxapine in the body, for example by inhalation.

  Loxapine [2-chloro-11 (4-methyl-1-piperazinyl) dibenzo (b, f) (1,4) oxazepine] is an anticancer drug particularly useful for the treatment of schizophrenia or related psychosis. It is a psychotic drug. This is commercially available in salt form, usually in the form of hydrochloride or succinate. Amoxapine [2-chloro-11 (1-piperazinyl) dibenzo (b, f) (1,4) oxazepine] is both an antidepressant and an antipsychotic in that it has the effect of an antidepressant. Different known antidepressants. Therefore, amoxapine is mainly used to treat psychotic depression, unlike other antidepressants.

  [0003] Several patents and literature suggest that pain can be treated to some extent with selected antipsychotics and / or antidepressants. However, the data supporting this assumption was scattered and interspersed, with some drugs showing varying degrees of pain control, but other compounds in the same pharmacological class were completely ineffective for pain control . Therefore, the actual overall picture is not clear.

  [0004] For example, US Pat. Nos. 5,929,070, 5,945,416, and 6,258,807, olanzapine alone or in combination for treating various types of pain The use is disclosed. US Pat. No. 6,444,665 describes several atypical antipsychotic compounds in the treatment of pain, particularly when administered with several other pain relieving drugs: risperidone, clozapine, quetiapine, sertindole, ziprasidone And the use of zotepine. On the other hand, according to other studies [Schreiber et al. (1999) Pharmacology Biochemistry Behavior 64:75], even among drugs of the same class (eg, olanzapine and clozapine), pain is observed between atypical antipsychotics. There are differences in the ability to control, thereby demonstrating that the analgesic effect is not the type of effect that antipsychotics normally have.

  [0005] US Patent No. 6,290,986 discloses the transdermal administration of various agents that control local pain in the form of special formulations containing lecithin organic gels. Several antidepressants, particularly amitriptyline and doxepin, have been disclosed for use in the form of such formulations. However, there are claims that this antidepressant is only effective when used in combination with the compound guaifenesin, which is known to have analgesic effects by itself, and the efficacy of this antidepressant when administered without guaifenesin There is no suggestion that there is. At the end of the text of this patent, an "opinion" is stated that many other tricyclic drugs, including amoxapine, will show similar activity. In a more recent patent of the same series, 6,479,074, amoxapine is useful in several transdermal compositions for the treatment of local pain, also administered in combination with guaifenesin. It is included in the list of so-called tricyclic compounds. However, no data on amoxapine has been reported. Similarly, US Pat. No. 6,638,981 claims that compositions containing antidepressants are effective in treating local pain using locally applied compositions because of the local anesthetic effect. Has been. However, it is not suggested in this patent that antidepressants show analgesic effects after systemic administration. There are 10 categories of antidepressants, including other or “all others” categories. Each category contains a very long list of compounds that probably have activity against pain. Amoxapine is listed in one of the many compounds belonging to one of this category, but again no data is given about it, in fact data on most of the compounds individually named in this patent Also not presented. In contrast, the data is concentrated on the two compounds amitriptyline and ketamine. US Pat. Nos. 5,900,249 and 6,211,171 also describe compounds where amoxapine is said to be useful for pain control when incorporated into a topical composition (eg, as a local anesthetic) However, no data on amoxapine is presented, and it is not suggested that antidepressants show analgesic effects after systemic administration.

  [0006] Lynch [“Antidepressants as analgesics: a review of randomized controlled trials” (2001) Reveal de Psychiatre et de Neuroscience Summarizing the results, he says, “There is significant evidence that the tricyclic antidepressant group is analgesic and not in trazodone, and the data on selective serotonin reuptake inhibitors are conflicting.” . However, even in the case of tricyclic antidepressants, the listed 41 references have only investigated five such compounds (amitriptyline, doxepin, imipramine, clomipramine and desipramine), and the mechanism of action There were no reports of loxapine and amoxapine that differed significantly from the compounds tested in.

  [0007] Briefly, a small number of antidepressants are shown to have some analgesic properties that control local pain or result in local anesthesia when applied primarily as a topical or transdermal composition. It was done. However, the efficacy of this compound was not related to its antidepressant activity and was not shown to represent any type of effect in that class. Furthermore, other studies [Hamon et al. (1987) Neuropharmacology 26: 531-539] showed that morphine's analgesic effect was promoted after long-term treatment with amoxapine in animal models, which suggests that amoxapine itself It suggested that it had no effect on pain. FIG. 1 of this reference shows that the duration of tail flick does not change after long-term administration of amoxapine alone, thereby suggesting that amoxapine alone has essentially no effect on pain. In another reference, Pfeiffer [(1982) Geriatrics 27:67] found that several tricyclic antidepressants, including amoxapine, “have good results in patients who are experiencing pain as a manifestation of depression. "It has said. Again, this can be distinguished in that this antidepressant is used to treat somatization of depression that manifests as pain rather than actual pain.

  [0008] Briefly, amoxapine is listed in many compounds (in some of the patents listed above) that are believed to have some such activity, but it has this ability. No data confirming this was presented, and one study indicated that such activity was lacking. Furthermore, unlike references that suggest that using antipsychotics can alleviate pain, several antipsychotics have actually been shown to provide the opposite effect of augmenting pain [Frussa- Filho et al. (1996) Arch Int Pharmacodyn 331: 74-93 (haloperidol) and Gleeson et al. (1982) Psychopharmacology 78: 141-146 (chlorpromazine)]. Even though amoxapine has the ability to control pain, especially the ability to control non-localized pain, it cannot be confirmed from this lack of information, and does loxapine have some kind of pain-suppressing effect of some nature? There is no information in the art about whether.

Brief summary of the invention

  [0009] The present invention includes treating or controlling pain by administering an effective amount of loxapine or amoxapine systemically or to the brain. Preferably, loxapine or amoxapine is administered by inhalation. The present invention also includes methods of administering loxapine or amoxapine to treat pain as described above, and formulations for such administration.

Detailed Description of the Invention

  [0012] Loxapine [2-chloro-11 (4-methyl-1-piperazinyl) dibenzo (b, f) (1,4) oxazepine] is an anticancer drug particularly useful for the treatment of schizophrenia or related psychosis. It is a psychotic drug. This is commercially available in salt form, usually in the form of hydrochloride or succinate. Amoxapine [2-chloro-11 (1-piperazinyl) dibenzo (b, f) (1,4) oxazepine] is a known antidepressant with antipsychotic properties.

  [0013] Neither loxapine nor amoxapine has previously been shown to be effective in treating or controlling pain. However, the inventors have discovered that these substances are surprisingly effective in treating or controlling pain, particularly headaches including migraine, tension headache and cluster headache.

  [0014] The treatment or control of pain according to the present invention is to treat a patient or subject in need of such treatment with amoxapine, loxapine, one of these pharmaceutically acceptable salts, or one of these prodrugs. Is achieved by administering an amount effective to reduce or alleviate. The use of a salt or prodrug of this active ingredient can provide an effective means of supplying the subject with an appropriate amount of loxapine or amoxapine, respectively, and the active ingredient can be formulated, packaged, or otherwise prepared and / or Benefits can be provided upon administration.

  [0015] In one aspect of the invention, a patient or subject is treated by administering an amount of loxapine or amoxapine or a pharmaceutically acceptable salt or prodrug of loxapine or amoxapine effective for pain relief. By “an amount effective for pain relief” is meant the amount of the substance in question that inhibits or prevents pain. The present invention can be applied to alleviate current pain as well as to suppress or prevent pain that should result from an event that causes imminent pain.

  [0016] The terms "relief", "suppression" and "inhibition" are used to alleviate and attenuate symptoms, further tolerate pain symptoms or conditions for the patient or subject, reduce the duration of pain, Refers to evidence of successful treatment or alleviation of pain, including objective and subjective parameters, such as delayed onset of pain expected to occur later. When referring to the treatment of headaches, including migraine, the terms `` relief '', `` suppression '' and `` prevention '' are used to alleviate and attenuate symptoms, further tolerate the headache for the patient or subject, reduce the duration of the headache , Refers to evidence of successful treatment or alleviation of any real headache or headache of any headache, including objective and subjective parameters, such as alleviation of headache expected following a headache, Pain (headache) frequency, unless reduction or prevention of pain (headache) is achieved, especially during the precursors of the headache or by using medication when the first signs of the headache appear This prevention of such a decrease in the incidence of pain (headache) is specifically excluded from this. That is, when it comes to the treatment of headaches, long-term use of the drug for the purpose of preventing headaches is specifically excluded from the terms “relaxing”, “suppressing” and “blocking”.

  [0017] As used herein, "pain" includes all types of pain. More specific types of pain included in this term include neuropathic pain, inflammatory pain, nociceptive pain, acute pain, chronic pain, local pain, systemic pain, postoperative pain, toothache, migraine, Cluster headache, tension headache, neuralgia, cancer pain, resistant pain, burn pain, labor and labor pain, postpartum pain, irritable bowel syndrome, fibromyalgia, pancreatic pain, pain due to myocardial infarction, As well as temporary mandibular abnormalities. Treatment of migraine, cluster headache, tension headache, and other types of pain, especially by systemic administration, by reaching an effective amount of loxapine or amoxapine or either salt or prodrug thereof to the central nervous system, Of particular importance to the present invention.

  [0018] The term "subject" or "patient" refers to mammals, including vertebrates, preferably primate mammals such as humans, and other animals including non-primate mammals such as pets and domestic animals. .

  [0019] The term "pharmaceutically acceptable salt" refers to an active compound prepared with a relatively non-toxic acid, depending on the particular substituents on the compounds described herein. Means containing salt. “Pharmaceutically acceptable” means that the salt in question has been approved by a federal, state or other foreign government supervisory authority for use in animals, and more specifically in humans. Means or can be described or may be described in the United States Pharmacopeia or other generally accepted pharmacopoeia. Since the compounds of the present invention contain relatively basic functional groups, the neutral form of such compounds can be contacted with a sufficient amount of the desired acid in the absence of a solvent or in a suitable inert solvent. Addition salts can be obtained. Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, iodide. Those derived from inorganic acids such as hydrogen acid, phosphorous acid, etc., as well as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid And salts derived from relatively non-toxic organic acids such as benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid, galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66, 1-19). See

  [0020] Starting from a salt, the neutral form of the compound can be regenerated by contacting the salt with a base [or acid] and isolating the parent compound in the conventional manner. The parent type compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent type compound for purposes of the present invention.

  [0021] In addition to salt forms, the present invention provides active compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under chemical, biochemical, or physiological conditions to provide loxapine or amoxapine, respectively. For example, prodrugs of loxapine or amoxapine can be hydrolyzed, oxidized, hydrogenated, cleaved, or otherwise reacted under biological conditions in vitro or in vivo to give the active compound. Possible compounds are included. Several phosphonooxymethyl prodrugs of loxapine have been described by Krise et al., J Pharm Sci. (1999) 88: 922 and 928, and J Med Chem. (1999) 42: 3094.

  [0022] Loxapine or amoxapine is generally less than is used for the current purpose of treating schizophrenia and depression, respectively, when used to treat a subject for pain relief, especially to treat migraine Use at dosage.

[0023] As described in the Physicians' Desk Reference (57th edition, 2003), the recommended initial oral dose of loxapine for the treatment of schizophrenia is 10-20 mg / day, 2-4 times a day Divide and administer. However, this dose is generally not effective and the dose is gradually increased, with the usual oral dose being 20-100 mg / day, typically 60-100 mg, up to 250 mg. A typical single acute dose is 20-50 mg. A typical daily intramuscular dose of loxapine is 50-150 mg for the treatment of severe psychiatric disorders (mainly schizophrenia), and usually the total dose is 2-4 times as with oral administration. Divide into two doses. Based on studies conducted by manufacturers of loxapine-containing products [Leddle Laboratories], the T _max after oral administration is 2-3 hours. Information about C _max after oral administration is controversial and the two research reports are in conflict. According to one report, the C _max of loxapine and its metabolites is about 0.35 μg / ml after 25 mg oral administration. However, according to different studies, the C _max of loxapine alone is about 10-12 ng / ml after 25 mg oral administration. There is no clear PK study of intramuscular formulations. However, behavioral observations should suggest that absorption is relatively slow.

  [0024] However, in the treatment of migraine according to the present invention, loxapine is administered at a dosage of about 0.3 to about 20 mg, preferably about 1 to about 10 mg, most preferably about 2 to about 6 mg per single dose. To do. In general, a single dose is effective during migraine attacks and does not need to be administered multiple times a day. In certain embodiments of the invention, the above amounts are administered as a series of smaller doses until migraine is reduced.

[0025] A typical daily oral dose of amoxapine in depression treatment is 200-400 mg. Treatment usually starts with an oral dose of 50 mg administered 3 times a day (ie, the total daily dose is 150 mg), with the dose being gradually increased. The T _max of amoxapine after oral administration is about 1.5 hours after 100 mg oral administration. The C _max after similar administration is about 50 ng / ml [Calvo et al., Int J Clin Pharmacol The Toxicol (1985) 23: 180]. After administration at the oral dose (50 mg) used at the lowest dose, the C _max is about 30 ng / ml [Jue et al., Drugs (1982) 24: 1]. After repeated administration of amoxapine, accumulation of active drug is observed, with blood concentrations of about 30-300 ng / ml (Calvo et al., 1985).

  [0026] However, in the treatment of migraine according to the present invention, amoxapine is administered at a dosage of about 3 to about 100 mg, preferably about 10 to about 40 mg per single dose.

  [0027] A composition comprising loxapine or amoxapine can also be administered to a patient or subject in any of a variety of ways that can be administered systemically. This includes administration by inhalation, parenteral administration, eg administration by injection (eg intradermal, intramuscular, intraperitoneal, intravenous, intrathecal or subcutaneous) and mucosal administration (eg intranasal, oral, or Rectal route). In a preferred embodiment of the present invention, the pharmaceutical composition comprising loxapine or amoxapine is not limited to nasal administration, sublingual administration (or other buccal administration), pulmonary administration (ie by inhaler, nebulizer, etc.) Administration by inhalation or injection, including mucosal administration, including pulmonary inhalation), rectal administration. The active ingredient can be administered alone, for example, with other biologically active agents as described in this section. Although it can be administered systemically or locally, it is preferably administered systemically. When topical, it is preferred to administer the drug directly to the brain via the nose, without first entering the systemic circulation. By passing the drug through the extracellular space in the olfactory tract, the drug can be put into the brain through the nose in this way.

  [0028] As described above, the pharmaceutical composition of the present invention is formulated to be compatible with the intended route of administration. As is well known in the art, different types of compositions are usually prepared for use by different routes of administration. In general, the composition comprises various excipients, additives and agents included for purposes such as stable storage, ease of administration and the like.

  [0029] For example, intravenous or other injectable compositions are usually solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lidocaine to reduce pain at the site of the injection.

  [0030] When the composition of the present invention is to be administered orally, it can be formulated, for example, in the form of tablets, capsules, cachets, gelcaps, solutions, suspensions and the like. Tablets or capsules may contain binders (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (eg magnesium stearate) , Talc or silica), disintegrants (eg, potato starch or sodium starch glycolate), wetting agents (eg, sodium lauryl sulfate) and the like, prepared by conventional means using pharmaceutically acceptable excipients. Can do. The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, and can be provided as water or other suitable solvent and the dry product thereof prior to use. Such liquid formulations include suspending agents (eg, sorbitol syrup, cellulose derivatives or hardened edible oil), emulsifiers (eg, lecithin or acacia), non-aqueous solvents (eg, almond oil, oily esters, ethyl alcohol or water Oils), preservatives (eg methyl or propyl-p-hydroxybenzoate or sorbic acid) and the like and can be prepared by conventional means using pharmaceutically acceptable additives. The formulation may also contain buffer salts, flavoring agents, coloring agents and sweetening agents as appropriate. Formulations for oral administration can be formulated to be suitable for slow release, controlled release or sustained release of prophylactic or therapeutic agent (s).

  [0031] The compositions of the invention can also be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Injectable preparations may be provided in unit dosage form, eg, in ampoules or in multi-dose containers, with a preservative added. The compositions can take the form of suspensions, solutions, emulsions in oily or aqueous solvents, and can contain pharmaceutical agents such as suspending, stabilizing, dispersing agents. Alternatively, the active ingredient may be in the form of a suitable solvent prior to use, such as sterile pyrogen-free water and a powder comprising it.

  [0032] If the composition of the present invention is to be administered mucosally from the nasal cavity, the composition can be formulated in the form of an aerosol, spray, mist, or drop. Specifically, the present invention in the form of an aerosol spray from a compressed pack or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Can be conveniently delivered. In the case of a compressed aerosol, the unit dose can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and capsules for use in an inhaler or insufflator can be made by placing a powder mixture of the compound and a suitable powder base such as lactose or starch.

  [0033] The compositions of the invention can also be formulated into rectal compositions containing conventional suppository bases such as suppositories or indwelling enemas, eg cocoa butter or other glycerides.

  [0034] The composition of the present invention can also be formulated for transdermal administration. The active compound can be formulated into ointments, salves, gels, or creams for transdermal administration as is generally known in the art. A pharmaceutical composition adapted for transdermal administration can be provided as a discontinuous patch intended for long-term close contact with the epidermis. When the composition of the present invention is to be administered topically, the composition may be, for example, in the form of an ointment, cream, transdermal patch, lotion, gel, spray, aerosol, liquid, emulsion, or the like. Other forms known to those skilled in the art can be formulated. For non-sprayable topical dosage forms, a viscous to semi-solid or solid form containing a carrier or one or more excipients compatible with topical application, preferably having a mechanical viscosity greater than water is usually used. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, smears, salves, etc., which are sterilized, if desired, or such as osmotic pressure, etc. It is mixed with adjuvants that affect various properties (eg preservatives, stabilizers, wetting agents, buffers, or salts). Other suitable topical dosage forms include aerosol formulations that can be nebulized, the active ingredient of which is preferably combined with a solid or liquid inert carrier and a compressed volatile substance (eg, a gas propellant such as chlorofluorocarbon). In the form of a mixture or in a squeeze bottle. If desired, humectants or wetting agents can be added to the pharmaceutical compositions and dosage forms. Examples of such additional components are well known in the art.

  [0035] The composition of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, using a suitable polymeric or hydrophobic material (eg, as an acceptable emulsion in oil), using an ion exchange resin, or as a slightly less soluble derivative, eg, as a slightly less soluble salt The composition can be formulated.

  [0036] In certain embodiments, the pharmaceutical composition can be delivered in a controlled release or sustained release system. In one embodiment, a controlled release or sustained release can be achieved with a pump (Langer, Science, 249: 1527-1533 (1990); Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:10). Buschwald et al., 1980, Surgery 88: 507; Saudek et al., 1989 N. Engl. J. Med. 321: 574). In other embodiments, polymeric materials can be used to achieve controlled or sustained release of the active ingredients (eg, Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida Drug 1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Macromol. Sci. Rev. Macrol. Chem. 23:61; Levy et al., 1985 Science 228: 190; During et al., 1989, Ann. Neurol. 25: 351; Howard et al., 1989, J. MoI. Neurosurg. 71: 105; U.S. Patent No. 5,679,377; U.S. Patent No. 5,916,597; U.S. Patent No. 5,912,015; U.S. Patent No. 5,989,463; U.S. Patent No. 5,128. 326; PCT Publication WO 99/12154; and PCT Publication WO 99/20253). Examples of polymers used in sustained release formulations include, but are not limited to, poly (2-hydroxyethyl methacrylate), poly (methyl methacrylate), poly (acrylic acid), poly (ethylene-co-acetic acid). Vinyl), poly (methacrylic acid), polyglycolide (PLG), polyanhydride, poly (N-vinylpyrrolidone), poly (vinyl alcohol), polyacrylamide, poly (ethylene glycol), polylactic acid (PLA), poly ( There are lactide-co-glycolide (PLGA), and polyorthoesters. In a preferred embodiment, the polymer used in the sustained release formulation is inert, free of filterable impurities, stable on storage, sterile, and biodegradable. In other embodiments, a controlled release or sustained release system can be installed in proximity to a therapeutic target, thereby requiring only a fraction of the systemic dose (eg, Goodson, Medical Applications of Controlled Release). Supra, vol. 2, pp. 115-138 (1984)).

  [0037] A preferred method of administration of loxapine and amoxapine, which is a feature of the present invention, is administration by inhalation or pulmonary administration. Drug delivery to the lung is achieved by several different approaches including liquid nebulizers, aerosol-based metered dose inhalers (MDI) and dry powder dispersers. The composition used for this type of administration is usually a dry powder or an aerosol. For aerosol administration, which is the preferred method of administration of the present invention, the composition is generally delivered by an inhaler. Several types of inhalers are described below.

  [0038] In addition to the active ingredient, the dry powder contains a carrier, an absorption enhancer, and optionally other ingredients. The carrier is, for example, a monosaccharide, disaccharide, polysaccharide, sugar alcohol or other polyol. Suitable carriers include lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, and starch. Lactose is preferred, especially in the monohydrate form. Absorption promoters such as polypeptides, surfactants, alkylglycosides, amine salts of fatty acids, phospholipids are also included. The formulation components usually must be in a fine form, ie their median particle size should generally be less than about 5-10 μm, preferably about 1 to about 1, as measured with a laser diffractometer or Coulter counter. 5 μm. Methods known in the art, such as grinding, refinement or direct precipitation can be used to achieve the desired particle size.

  [0039] For administration by inhalation, the compounds according to the invention are conveniently delivered in the form of a concentrated aerosol, as discussed in US patent application Ser. No. 10 / 152,639 filed May 20, 2003. This application is incorporated herein by reference in its entirety. Inhalation or pulmonary administration of loxapine or amoxapine in an aerosol dosage form is preferred for use in the present invention, and preferably the aerosol has an aerodynamic median particle size (MMAD) of from about 0.01 to about 3 μm. Such aerosols can be made from a thin film of the drug, and the thin film itself can be made using a drug solution in a suitable solvent or a melt of the drug itself. The membrane is preferably about 0.05 to about 20 μm thick, but a particularly suitable device for making loxapine and amoxapine aerosols from such a thin film is filed on Aug. 4, 2003, Pending US patent application 10 / 633,877, entitled “Thin-Film Drug Delivery Article and Method of Use”, and “Rapid-Heating Drug Delivery University” filed August 4, 2003. No. 10 / 633,876, pending application, both of which are hereby incorporated by reference in their entirety. Preparation of such an aerosol is preferably carried out under vaporization conditions sufficient for the recovery rate of the active ingredient to be at least 50% in the aerosol, wherein the decomposition product of the compound contained in the aerosol is about 5% by weight. %.

  [0040] When using amoxapine and loxapine for the treatment of headache, especially migraine attacks, preferably within 30 minutes, more preferably within 15 minutes, most preferably within 5 minutes of administering the drug. It is preferred to deliver amoxapine or loxapine rapidly so that a maximum plasma concentration occurs. Such rapid drug absorption is achieved by routes including intravenous delivery or aerosol inhalation, but again aerosol administration is the preferred route.

  [0041] More specifically, with respect to migraine treatment, the present invention relates to a method of delivering loxapine that reaches a maximum drug blood concentration within 30 minutes of administration, preferably within 15 minutes of administration. provide. In this way, the peak rate of increase of loxapine blood concentration can be at least 1 ng / ml / min, and the blood concentration of loxapine can be at least 5 ng / ml within 15 minutes of administration.

  [0042] With respect to migraine treatment using amoxapine, the present invention also provides delivery of amoxapine to reach the maximum blood concentration of amoxapine within 30 minutes of administration, preferably within 15 minutes of administration. Provide a method. When this is done, the peak rate of increase in blood concentration of amoxapine will be at least 3 ng / ml / min and within 15 minutes of administration, the blood concentration of amoxapine may be at least 10 ng / ml.

  [0043] This rapid reaching of the drug concentration is preferably achieved by creating an aerosol from a thin film of drug, most preferably for the thin film and rapid heating disclosed in the two patent applications mentioned above. This is achieved by using the device.

  [0044] The composition of the present invention may be used as one or more other therapeutic agents as long as the pain relieving action of loxapine or amoxapine is not inhibited or an undesirable combination effect is not produced even when administered in combination. Can be used in combination therapy. Loxapine or amoxapine and other therapeutic agents can act additively or synergistically. In a preferred embodiment, the composition of the invention is administered concurrently with the administration of other therapeutic agents. The agent may be part of the same composition comprising loxapine or amoxapine of the present invention or in a different composition. In other embodiments, loxapine or amoxapine is administered before or after administration of the other therapeutic agent. In one embodiment of a combination therapy involved in the treatment of chronic pain, the combination therapy includes a composition comprising loxapine or amoxapine and another therapeutic agent to minimize toxicity associated with the particular agent. Things are administered alternately. One administration duration may be, for example, 1 month, 3 months, 6 months, 1 year, or longer. In certain embodiments, when a compound of the present invention is administered concurrently with other therapeutic agents that may potentially cause adverse side effects, including but not limited to toxicity, advantageously, adverse side effects are induced. The therapeutic agent can be administered at a dose that is less than the threshold that is administered.

  [0045] For example, loxapine or amoxapine can be combined with other analgesics such as opioids, non-steroidal anti-inflammatory drugs (NSAIDs), etc. in dosage forms in the amounts or dosages of the present invention. Is hydromorphone, codeine, morphine, nicomorphine, hydroxycodone, fentanyl, aspirin, ibuprofen, diclofenac, naproxen, benoxapolfen, flurbiprofen, fenoprofen, ketoprofen, indoprofen, carpolfen, oxaprozin, suprofen, thiaprofen Acid, indomethacin, sulindac, tolmetin, zomepirac, acemetacin, fenthiaza, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, piroxicam, isoxy Beam or a pharmaceutically acceptable salt thereof, prodrugs or mixtures thereof. Other suitable analgesics that can be included in the dosage forms of the present invention include steroidal anti-inflammatory agents such as glucocorticoids, dexamethasone (DECADRON ™), cortisone, hydrocortisone, prednisone, prednisolone, Triamcinolone; eicosanoids such as prostaglandins, thromboxanes, leukotrienes; salicylic acid derivatives including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine; acetaminophen and Paraaminophenol derivatives including phenacetin; indole and indene acetic acid including indomethacin, sulindac, and etodolac; celecoxib, lof Cyclooxygenase 2 specific inhibitors including coxib, valdecoxib, eterocoxib and parecoxib; heteroaryl acetic acid including tolmethine and ketorolac; anthranilic acid including mefenamic acid and meclofenamic acid; oxicam (eg piroxicam or tenoxicam), and Enolic acids including pyrazolidinediones (eg, phenylbutazone); and alkanones including nabumetone.

  [0046] Loxapine or amoxapine is also alpiropride, dihydroergotamine, dolasetron, ergocornin, ergocorninin, ergocriptine, ergot, ergotamine, phonazine, lisuride, lomerizine, methysergide, oxetrone, pizotirin, sumatriptan, lazatriptan, lazatriptan, It can also be formulated into pharmaceutical dosage forms in combination with other anti-migraine agents such as eletriptan, frovatriptan, donitriptan, zolmitriptan, mixtures thereof and the like.

  [0047] Loxapine or amoxapine can also be formulated into a pharmaceutical dosage form in combination with an antidepressant. Suitable antidepressants include, but are not limited to, caroxazone, citalopram, dimesazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxypertin, paroxetine, sertraline, thiazesim, trazodone, iproclozide, iproniazide, isocarboxazi , Octamoxine, phenelzine, cotinine, rolipram, maprotirin, metralindole, mianserin, mirtazepine, azinazolam, amitriptyline, amitriptylinoxide, buttriptyline, clomipramine, demexeptiline, desipramine, dibenzepin, dimethacrine, doxepin, flumidin Oxide, iprindol, lofepramine, melitracene, metapramine, Triptyline, Noxiptylline, Opipramol, Pizotirin, Propizepine, Protriptyline, Quinupramine, Tianeptine, Trimipramine, Adrafinil, Benactidine, Bupropion, Butacetin, Dioxadrol, Duloxetine, Etoperidone, Fevalbamate, Femoxetine, Fenxetol, Fenpentadiol, Fentadiol Hematoporphyrin, hypericin, levofacetoperan, minaprine, moclobemide, nefazodone, oxafurozan, piberalin, prolintane, pilanseride, roxindole, rubidium chloride, sulpiride, tandospirone, sozalinone, tofenacin, troxatone, tranolcipromine, L -Tryptophan, venlafaxine, viloxa Down, and there is a zimeldine.

  [0048] Similarly, loxapine or amoxapine can also be combined with antiepileptic agents such as valproate, phenytoin, phenobarbital, primidone carbamazepine, ethosuximide or clonazepam.

  [0049] The following examples further illustrate the invention described herein and are not intended to limit the scope of the invention in any way.

Actual example
Example 1
Mouse postcard (rising) behavior test
[0050] Male mice weighing 23-28 g were used in this study. Mice were injected with acetic acid (0.5%, intraperitoneal). This treatment induces a recognizable stroking response in control animals. Count the number of postcards for 10 minutes starting 5 minutes after acetic acid injection. Ten mice per group were tested. The test was performed blind. Five doses of loxapine and amoxapine (dispersed in 0.2% hydroxypropylmethylcellulose and then dissolved in saline), administered intraperitoneally 30 minutes prior to acetic acid, were evaluated and this was evaluated as a solvent control (0 .2% hydroxypropyl methylcellulose in saline solution) group. The dose of loxapine was 0.125, 0.25, 0.5, 1 and 2 mg / kg body weight. Amoxapine doses were 1, 2, 4, 8 and 16 mg / kg body weight. Morphine (8 mg / kg, ip) was administered under the same experimental conditions and used as a reference substance. Data was analyzed by comparing treatment groups to vehicle controls using the Mann-Whitney U test.

  [0051] Table 1 shows the results.

  [0052] As shown in Table 1, amoxapine decreased the number of stroking behaviors induced by acetic acid in a dose-dependent manner, and a significant decrease was observed from 2 mg / kg. The effect was clearly recognized from 4 mg / kg. Loxapine reduced the number of stroking behaviors induced by acetic acid in a dose-dependent manner, with a significant reduction seen from 0.125 mg / kg. The effect was remarkably recognized from 0.25 mg / kg. Sedation was observed from 2 mg / kg for amoxapine and from 0.25 mg / kg for loxapine. Morphine showed significant antagonism against stroking behavior induced by acetic acid in each experiment.

Example 2
Acute and 5-day repeated dose toxicity studies of inhalable aerosol formulations of loxapine in beagle dogs
[0053] The purpose of this study was to examine the maximum toxicity of each individual and the potential toxicity of loxapine at two clinically relevant doses in a 5-day repeated dose study in dogs.

  [0054] This study was performed in CTBR located at 87 Senneville Road, Senneville, Quebec, Canada, H9X3R3, according to the CTBR's Standard Operating Procedures.

  [0055] The test article was a loxapine aerosol delivered by oropharyngeal inhalation.

  [0056] The animals used were Beagle dogs purchased from Covance Research Product at Route 2, Box 113, Cumberland, VA 23040, and were approximately 7-10 months old and 6-12 kg at the start of treatment. Animals were housed independently in stainless steel cages with a bar-type floor and an automatic water supply valve. Each cage was clearly categorized with a color-coded tag indicating the plan, group, animal, tattoo number and gender. Each animal was uniquely identified by a permanent tattoo number and / or letter on the ventral side of one pinna.

  [0057] The animal room environment and photoperiod conditions were as follows.

  [0058] Except during the specified procedure, all animals have free access to a certified standard commercial granular canine diet (400 g, PMI Certified Dog Chow 5007: PMI Nutrition International Inc.). I let you.

  [0059] The maximum allowable concentration of contaminants (eg, heavy metals, aflatoxins, organophosphates, chlorinated hydrocarbons, PCBs) in the diet was controlled.

  [0060] Public tap water was softened, purified by reverse osmosis, and allowed to drink whatever was irradiated with ultraviolet light (except during the designated procedure).

  [0061] An acclimatization period of about 3 weeks was allowed from the time the animal was received to the start of treatment in order to accustom the animal to the experimental environment.

  [0062] Prior to initiating treatment, all animals were weighed and animals were assigned to each treatment group using a randomized procedure. Randomization was performed by stratification using body weight as a parameter. Males and females were randomized separately. The final animal assignment was confirmed to ensure that litters were evenly distributed across all groups.

  [0063] Animals were assigned to the following groups: Repeated administration of loxapine 2 mg / kg (2 males, 2 females), repeated administration of loxapine 0.2 mg / kg (2 males, 2 females), repeated solvent control (2 males, 2 females), Single incremental dose of loxapine (1 male, 1 female) at least 48 hours apart.

  [0064] Animals were treated with the test aerosol using an oropharyngeal facial mask fitted with infusion and drainage tubes. Animals were placed in restraining slings during treatment.

  [0065] A mask was used that allowed the dog to inhale the test substance. The mask consisted of a plastic cylinder with the nose inside the cylinder and attached to the nose of the dog so that the animal could breathe through a short tube. By vaporizing loxapine by heating a thin film of loxapine about 4 microns thick formed on the foil to approximately 400 ° C. by immersing and coating the stainless steel foil in a loxapine solution dissolved in an organic solvent. A test article was produced. The aerosol agent obtained by concentrating the vaporized loxapine was introduced into the mixing chamber by pre-dried compressed air. The mixing chamber was operated under slightly positive pressure maintained using a gate valve installed in the exhaust path. Using a vacuum pump, the inhalation chamber was evacuated at the required flow rate and contaminated air (excess aerosol and exhalation) was pumped through a purification system consisting of a 5 μm coarse filter before exhausting air from the structure. . The resulting atmosphere was delivered to the dog mask via the delivery tube.

  [0066] The solvent control group was exposed to pre-dried compressed air that passed through a drug heater containing clean stainless steel foil instead of loxapine-coated foil. Repeated administration group of 2 mg / kg in that air is passed through the operating device or heating device, except that there is no drug, so that the dog can only breathe through the dog mask, and the dog is also restrained and handled Exposed to air under the same conditions.

  [0067] To ensure that the dosage was accurate, the atmosphere of the test article aerosol was characterized before the start of treatment each day. The operating conditions of the system for exposure to the drug required to establish each target aerosol concentration are determined from a single-sided glass fiber filter sample collected from a representative mask for exposure of the animal to the drug. Determined by measurement method.

  [0068] It was also determined that the atmospheric concentration in the chamber was uniform when the dose of loxapine was 0.2 mg / kg and 2 mg / kg. This involved collecting two sets of filter samples for gravimetric analysis from two equally spaced dog breathing ports located near the periphery of the mixing chamber. Additional samples were also collected from the reference port to assess the overall distribution of the test article within the chamber and its variation within the port. The results obtained from this analysis demonstrated that the distribution of the aerosol was uniform.

  [0069] Analysis of aerosol particle size distribution at each loxapine dose was performed using a cascade impactor. This method consists of classification into a series of size ranges followed by a gravimetric analysis. The median particle size and its geometric standard deviation (MMAD ± GSD) were calculated from the gravimetric data using a computer program based on Andersen Operating Manual TR # 76-900016. The typical aerodynamic median particle size and GSD measured during the test was 1.4 μm ± 2.2.

  [0070] From the sampling port in the area where the animal breathed, the excretion concentration at the actual aerosol mask was measured at least once on each day exposed to the drug using gravimetric methods.

  [0071] The actual dose (mg / kg / day) of the active ingredient at each treatment level was determined as follows.

  [0072] Measurements were made twice for each animal prior to the first drug treatment using a Buxco Electronics LS-20 system.

  [0073] An example of calculating the actual dose of the active ingredient on a specific day of incremental administration as part of the study is as follows.

  [0074] Average chamber aerosol concentration: 0.489 mg / L

  [0075] MMAD ± GSD: 1.1 μm ± 2.2. Witschi & Nettesheim, Mechanisms in Respiratory Toxiology, Vol. 1: 54-56, CRC Press, Inc. Based on 1982. From the above MMAD and GSD, the precipitation ratio (D) is 0.38.

  [0076] Average BW: 8.3 kg

  [0077] Average RMV before test: 7.86 L / min (assuming no change during test)

  [0078] Exposure time: 15 minutes

  [0079] When the above data is applied to the formulas in the above table, the actual dose is 2.6 mg / kg.

  [0080] Dogs were treated with loxapine aerosols using the procedure described above for delivering aerosols and calculating the delivered dose. Initially, loxapine was administered to 1 male and 1 female at a dose of 1 mg / kg, but no change was observed in animal behavior. Several days later, when loxapine was administered 2.6 mg / kg to the same animal, weakness, tremor, and decreased activity were observed.

  [0081] Subsequently, as described above, two male dogs and two female dogs were administered the control vehicle for 5 days. This dog showed no change in behavior. Furthermore, loxapine was administered to 2 male dogs and 2 female dogs at 0.2 mg / kg (per day) for 5 days. This dog showed no change in behavior. Finally, loxapine was administered to 2 male dogs and 2 female dogs at 2 mg / kg (per day) for 5 days. The dog showed weakness, tremor, and decreased activity, but no adverse respiration findings such as cough. In particular, there were no signs of bronchoconstriction such as wheezing, prolonged expiratory phase, or cough. Feed consumption was approximately normal in all animals.

  [0082] At the end of the treatment period, animals were necropsied by incision and exsanguination of the axillary or femoral artery after anesthesia by intravenous injection of sodium pentobarbital. The sedative pharmacopoeia (USP) ketamine hydrochloride and xylazine for injection were administered by intramuscular injection before the animals were transported from the animal room to the autopsy area. To avoid changes due to autolysis, all euthanized animals were immediately subjected to complete pathological examination of the carcass. All animals did not receive food one night before the scheduled necropsy. There were no treatment-related findings in any animal during the autopsy. Histopathology was performed on any gross lesions. Again, no findings related to treatment were found. In addition, histopathological examination of the lung including the larynx, trachea, main bronchus and bronchi was performed. There were no treatment-related abnormalities.

  [0083] On the first day of repeated administration (day 5), which is part of the study, for toxicokinetic analysis, before administration, 2 minutes after the start of administration, immediately after administration, 20 minutes after administration, 1 hour, Plasma samples were collected after 3 hours, 9 hours and 24 hours. Samples were stored at −80 ° C. until loxapine plasma concentration analysis. Loxapine plasma concentration can be measured using analytical methods well known in the art, such as LC / MS, LC / MS / MS, and / or GC / MS. Predictive representative loxapine toxicokinetic data is provided in FIGS. In this data, it should be noted that loxapine plasma concentration rises very rapidly after administration of loxapine aerosol and a peak plasma concentration is obtained within 2 minutes after the end of drug inhalation. The rate of increase in loxapine plasma concentration averaged at least 70 ng / mL / min when exceeding the first 2 minutes of administration at a dose of 2 mg / kg and 20 ng when exceeding the first 10 minutes of administration at a dose of 2 mg / kg / ML / min is observed. The rate of increase in loxapine plasma concentration was at least 7 ng / mL / min on average over the first 2 minutes of administration at a dose of 0.2 mg / kg, and the first 10 minutes of administration at a dose of 0.2 mg / kg. When exceeded, it is observed to be 2 ng / mL / min. A therapeutic plasma concentration of at least 0.5 ng / mL, 1 ng / mL, 2 ng / mL, 4 ng / mL, 8 ng / mL, or 15 ng / mL, either dose within 10 minutes, 5 minutes Within 2 minutes.

Prediction example
Example 3
Phase I clinical trial of loxapine concentrated aerosol
[0084] A hand-held concentrated aerosol generator disclosed in US patent application 10 / 633,876 entitled "Rapid-Heating Drug Delivery and Method of Use" filed Aug. 4, 2003 is incorporated herein by reference. The loxapine-enriched aerosol is coated with loxapine to release 0, 2.5 mg, 5 mg or 10 mg (depending on the thickness of the coating) in less than 1 second after the device is activated.

  [0085] Generally, healthy volunteers who are 18 to 45 years old and have no serious mental illness, neurological disease, lung disease, renal disease or cardiovascular disease are recruited and participated in this study. Explain the potential risk of inhaling loxapine and seek informed consent. Those who agree will be enrolled in this study and will receive an intravenous catheter for the volunteer.

  [0086] Next, a hand-held device is given to the applicant. Prior to providing the device, the volunteer may or may not be trained in breathing techniques suitable for use of the device. At a minimum, each volunteer is instructed to exhale completely, then attach the device to the lips, take a long and deep inhalation, and hold it for a few seconds before exhaling. The volunteer then uses the device to administer the prescribed amount of loxapine concentrated aerosol. Volunteers and medical personnel conducting the study do not need to know the dose of the drug and whether the drug has been replaced with a placebo (ie a device with loxapine at 0 mg). Good.

[0087] About 0.3 minutes, 1 minute, 3 minutes, 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 360 minutes, 500 minutes, 750 minutes, and 1000 minutes after administration, venous blood Obtain a sample. Established methods described in the literature on loxapine are used to determine plasma drug concentrations. This analysis reveals that T _max is less than 10 minutes and that T _max normally appears in the sample after 3 minutes or in the sample after 1 minute. The bioavailability of concentrated aerosol delivery is higher than 35% and often higher than 55%.

[0088] The table below provides exemplary predicted _Cmax values at various doses.

Example 4
Phase II clinical trial of loxapine for the treatment of acute migraine attacks
[0089] The method of this study is a double-blind randomized placebo-controlled dose range setting study. Healthy men and women aged between 18 and 65, including age at both ends, self-reported moderate to severe migraine (with or without aura), 1 in the past 3 months Subjects with seizures with an average frequency of 1-6 times per month are recruited to participate in the study. Subjects who meet the inclusion criteria are enrolled and randomized to receive one of the following treatments: Placebo administration, about 1.25 mg administered with loxapine rapid delivery system, about 2.5 mg administered with loxapine rapid delivery system, about 5 mg administered with loxapine rapid delivery system, about 10 mg administered with loxapine rapid delivery system. Higher doses of loxapine can also be tested if found to be safe in phase I clinical trials. Loxapine rapid delivery system is a means of delivering loxapine to migraine patients so that the maximum plasma drug concentration can be obtained within 1 hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes and even 2 minutes or less It is. The concentrated aerosol delivery system described above for Phase I clinical trials is one such system. Other rapid delivery systems include various durations of intravenous infusion or injection.

  [0090] Immediately before treatment in a randomized patient, the patient was given a light on their headache and nausea severity on a 4-point scale (0: asymptomatic, 1: mild, 2: moderate, 3: severe). Two-point scale for phobia and sound phobia (0: No, 1: Yes when asked if light causes severe headache; 0: No, 1: Yes when asked if noise causes severe headache ). Alternatively, an 11-point visual analog scale (0: asymptomatic to 10: most severe) can be used, and other suitable scales can be used. Subjects are asked to repeat this assessment at 15 and 30 minutes after treatment and at 1, 2, 4, 8, 12, and 24 hours after treatment. Ask the subject to perform a comprehensive assessment of the subject on treatment efficacy (1: very poor to 5: very good) at 120 minutes and 24 hours after treatment. Record any medications you may be using.

  [0091] Groups administered loxapine 5 mg and 10 mg show a strong therapeutic effect of the drug within 1 hour. Specifically, at 1 hour, at 30 minutes, or even at 15 minutes, the severity of the headache of the treated patient is significantly lower than before treatment. Compared to 5 mg or 10 mg and placebo in terms of reducing headache in 1 hour, patients treated with loxapine showed a significant advantage, indicating that (with an appropriately sized sample size Assumed) low migraine score, low nausea score, low incidence of photophobia and sound phobia, greatly reduced headache score from baseline headache score, mild headache or no headache This is demonstrated by the statistically significant (at the p <0.05 level) of drug administration over placebo administration in that the proportion of patients is high and the proportion of patients without headache is high. This advantage persists at 2, 4, 8 and even 24 hours unless a rescuer is administered to the placebo-treated patient. Similar effects can be observed at a dose of 1.25 mg or 2.5 using an appropriately sized sample, but it may be difficult to collect an appropriately sized patient sample at this dose ( Need more patients because the effect may not be strong). Also, doses lower than 1.25 mg or 2.5 mg may require a longer duration (eg, 1 hour instead of 30 minutes) for the drug to be effective.

Example 5
Clinical use of loxapine for the treatment of acute migraine attacks
[0092] A 35-year-old woman, usually in good health, notices that moderate pain localized to the right side of the head occurred at home and lasted for about 10 minutes. In the next 10 minutes, the pain becomes more severe and throbbing. The woman recognizes this as a migraine, and if such a headache is not treated, it tends to last at least a whole day, resulting in nausea associated with the headache, and the pain is very severe You will also find it difficult or impossible to sleep. The woman turns off the light in the living room to avoid pain caused by bright light entering her eyes, and turns off the radio because the sound of the radio makes her headache worse. She drinks a 25 mg loxapine tablet from the mouth with a glass of water. In the next 15 minutes, the headache begins to worsen and the woman's stomach feels a little worse. However, in the next hour, the headache slowly slows down and the woman gets tired. I don't care about my stomach anymore. She slaps a little and wakes up without any signs of headache. Light and sound are no longer bothersome. She eats a normal meal without stomach upset. The headache does not reoccur in the next 72 hours and no further medication is required.

  [0093] The examples and embodiments described herein are for illustrative purposes only, and various modifications or variations have been suggested to those skilled in the art in light of the spirit, scope, It should also be understood that it should be included within the scope of the appended claims.

  [0094] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

It is a figure which shows the loxapine plasma density | concentration (ng / mL) in each elapsed time after the start of the administration of loxapine by inhalation with a dosage of 2 mg / kg in a beagle dog. It is a figure which shows the loxapine plasma density | concentration (ng / mL) in each elapsed time after the start of the administration of loxapine by inhalation with a dose of 0.2 mg / kg in a beagle dog.

Claims (24)

  A method of treating pain in a subject comprising administering to said subject an effective amount of a compound selected from the group consisting of loxapine, a pharmaceutically acceptable salt of loxapine and a prodrug of loxapine.   The method of claim 1, wherein the effective amount is an amount sufficient to reduce pain present in the subject.   The method of claim 1, wherein the compound is administered systemically.   The method of claim 1, wherein the pain is selected from the group consisting of migraine, cluster headache, and tension headache.   The method of claim 4, wherein the pain is migraine.   The method of claim 4, wherein the pain is cluster headache.   The method of claim 4, wherein the pain is tension headache.   The method of claim 1, wherein the compound is administered by inhalation.   The method of claim 1, wherein the subject is a human, the pain is migraine, and the compound is administered by inhalation.   Administering a salt or prodrug of loxapine in an amount that produces about 0.3 to about 20 mg of loxapine, or an amount that results in the same blood concentration of loxapine in a subject as if about 0.3 to about 20 mg of loxapine was administered; The method according to 1.   2. The method of claim 1, wherein about 1 to about 10 mg of loxapine is administered, or an amount of loxapine salt or prodrug is administered to the subject that results in the same blood concentration of loxapine as about 1 to about 10 mg of loxapine. .   11. The method of claim 10, wherein the administration of loxapine or a salt or prodrug thereof to the subject is performed to achieve a maximum blood concentration of loxapine within about 30 minutes after said administration.   11. The method of claim 10, wherein the administration of loxapine or a salt or prodrug thereof to the subject is performed to achieve a maximum blood concentration of loxapine within about 15 minutes after said administration.   11. The method of claim 10, wherein the administration of loxapine or a salt or prodrug thereof to the subject is performed such that the peak rate of increase in blood concentration of loxapine is at least about 1 ng / ml / min.   11. The method of claim 10, wherein the administration of loxapine or a salt or prodrug thereof to the subject is performed such that the blood concentration of loxapine is at least about 5 ng / ml within about 15 minutes after the administration.   The method of claim 1, wherein the compound is administered by inhalation using a rapidly heated drug delivery article or a thin film drug delivery article.   The vaporized and concentrated compound is administered by an inhalation delivery device so as to provide at least 50% recovery of the compound in the aerosol and less than about 5% by weight of the degradation products of the compound contained in the aerosol. The method according to claim 1.   The method of claim 17, wherein the compound is coated on a substrate in a delivery device as a thin film having a thickness of about 0.5-20 μm.   The method of claim 1, wherein the compound is administered in the form of an aerosol having an aerodynamic median particle size (MMAD) of about 0.01 to about 3 μm.   The compound vaporized from the compound composition film under conditions sufficient to provide an aerosol with a recovery of the compound of at least 50% and a degradation product of the compound included of less than about 10% by weight, 2. The method of claim 1, wherein the method is administered by a rapid heating drug delivery article.   A composition for treating pain, wherein said composition comprises (a) loxapine, a pharmaceutically acceptable salt thereof, and a prodrug amount of an analgesic amount selected from the group consisting of And (b) a pharmaceutically acceptable carrier.   24. The composition of claim 21, further comprising one or more analgesics, anti-inflammatory agents or anti-migraine agents.   A thin film composition for treating pain, comprising an analgesic amount of a compound selected from the group consisting of loxapine, a pharmaceutically acceptable salt thereof, and a prodrug thereof, and the thickness of the film A thin film composition having a thickness of about 0.5 to about 20 μm. A method of treating a headache in a subject comprising administering to said subject an effective amount of a compound selected from the group consisting of loxapine, a pharmaceutically acceptable salt of loxapine and a prodrug of loxapine.

Images